PKC and neurofibromin in the molecular pathology of urinary bladder carcinoma : the effect of PKC inhibitors on carcinoma cell junctions, movement and death
1University of Oulu, Faculty of Medicine, Department of Anatomy and Cell Biology
2University of Oulu, Faculty of Medicine, Department of Dermatology and Venereology
3University of Turku, Faculty of Medicine
4University of Turku, Faculty of Medicine, Department of Surgery
5University of Turku, Faculty of Medicine, Department of Medical Biochemistry and Molecular Biology
6University of Turku, Faculty of Medicine, Department of Anatomy
|Online Access:||PDF Full Text (PDF, 1.6 MB)|
|Persistent link:|| http://urn.fi/urn:isbn:9789514285899
|Publish Date:|| 2007-10-16
|Thesis type:||Doctoral Dissertation
|Defence Note:||Academic dissertation to be presented, with the assent of the Faculty of Medicine of the University of Oulu, for public defence in the Auditorium of the Department of Anatomy and Cell Biology, on October 26th, 2007, at 12 noon
Docent Johanna Ivaska
Docent Antti Kaipia
This study examined the role of tumor suppressor neurofibromin and Protein kinase C (PKC) in urinary bladder cancer, and the effect of PKC inhibitors on cancer cell behaviour.
Tumor suppressor protein neurofibromin is a product of the NF1 gene, a mutation of which causes the most common hereditary tumor syndrome, type 1 neurofibromatosis. NF1 gene mutations and changes in expression have been demonstrated in malignancies, unrelated to type 1 neurofibromatosis. The best known function of neurofibromin is its Ras GTPase accelerating function. Thus, it functions as a Ras inactivator. This study demonstrated for the first time that the NF1 gene is expressed in normal and malignant urinary bladder epithelium and in cultured bladder carcinoma cells in mRNA and at the protein level. Furthermore, neurofibromin expression is decreased during bladder carcinogenesis. It can be speculated that this may lead to increased Ras activity in urinary bladder cancer.
The PKC family is composed of several different isoenzymes which are responsible for a number of important intracellular events and cellular functions. Many of these are also important in cancer development and progression. The results demonstrate changes in expression of PKC α and βI isoenzymes in urinary bladder carcinoma. Furthermore, the results relate the increased expression of isoenzymes to increased PKC enzyme activity and the high proliferation rate of the cancer cells. In addition, this study utilizes small molecular inhibitors of PKC isoenzymes in order to study the effect of the inhibition of these isoenzymes on cancer cell behaviour in vitro and in vivo. The study mainly focuses on the function of PKC α and βI isoenzymes and on the effects of inhibition of these by using Go6976. The results show that Go6976 inhibits cancer cell growth, migration and invasion in vitro, and tumor growth in a mouse model. The use of Go6976 induces changes in desmosomes and adherens junctions, and in focal adhesions and hemidesmosomes. The results also show that Go6976 functions as a cell cycle checkpoint abrogator and increases the cytotoxicity of two classical chemotherapeutic agents, doxorubicin and paclitaxel. In the future, it may be possible that Go6976 or related drugs could be used in clinical cancer treatments.
Acta Universitatis Ouluensis. D, Medica
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